{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T02:58:55Z","timestamp":1771901935315,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,23]],"date-time":"2022-08-23T00:00:00Z","timestamp":1661212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["EI 423\/4-1"],"award-info":[{"award-number":["EI 423\/4-1"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG)","award":["MA 1289\/8-1"],"award-info":[{"award-number":["MA 1289\/8-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>The replication of human cytomegalovirus (HCMV) involves a process termed nuclear egress, which enables translocation of newly formed viral capsids from the nucleus into the cytoplasm. The HCMV core nuclear egress complex (core NEC), a heterodimer of viral proteins pUL50 and pUL53, is therefore considered a promising target for new antiviral drugs. We have recently shown that a 29-mer peptide presenting an N-terminal alpha-helical hook-like segment of pUL53, through which pUL53 interacts with pUL50, binds to pUL50 with high affinity, and inhibits the pUL50\u2013pUL53 interaction in vitro. Here, we show that this peptide is also able to interfere with HCMV infection of cells, as well as with core NEC formation in HCMV-infected cells. As the target of the peptide, i.e., the pUL50\u2013pUL53 interaction, is localized at the inner nuclear membrane of the cell, the peptide had to be equipped with translocation moieties that facilitate peptide uptake into the cell and the nucleus, respectively. For the resulting fusion peptide (NLS-CPP-Hook), specific cellular and nuclear uptake into HFF cells, as well as inhibition of infection with HCMV, could be demonstrated, further substantiating the HCMV core NEC as a potential antiviral target.<\/jats:p>","DOI":"10.3390\/ph15091040","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T00:22:48Z","timestamp":1661300568000},"page":"1040","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A Peptide Inhibitor of the Human Cytomegalovirus Core Nuclear Egress Complex"],"prefix":"10.3390","volume":"15","author":[{"given":"Sewar","family":"Alkhashrom","sequence":"first","affiliation":[{"name":"Department of Chemistry and Pharmacy, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91058 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jintawee","family":"Kicuntod","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Molecular Virology, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Stillger","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Institute of Biochemistry, University of Cologne, 50674 K\u00f6ln, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamara","family":"L\u00fctzenburg","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Institute of Biochemistry, University of Cologne, 50674 K\u00f6ln, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Anzenhofer","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Pharmacy, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91058 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6450-3991","authenticated-orcid":false,"given":"Ines","family":"Neundorf","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Institute of Biochemistry, University of Cologne, 50674 K\u00f6ln, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manfred","family":"Marschall","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Molecular Virology, Universit\u00e4tsklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6683-9456","authenticated-orcid":false,"given":"Jutta","family":"Eichler","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Pharmacy, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91058 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13027-015-0039-4","article-title":"Cytomegalovirus reactivation and its clinical impact in patients with solid tumors","volume":"10","author":"Schlick","year":"2015","journal-title":"Infect. Agents Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1159\/000322141","article-title":"Human Cytomegalovirus (HCMV)\u2014Revised","volume":"37","author":"Schottstedt","year":"2010","journal-title":"Transfus. Med. Hemother."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"201","DOI":"10.2174\/187152609787847758","article-title":"Drug Targets in Cytomegalovirus Infection","volume":"9","author":"Andrei","year":"2009","journal-title":"Infect. Disord. Drug Targets"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/pin.12502","article-title":"Pathogenesis of developmental anomalies of the central nervous system induced by congenital cytomegalovirus infection","volume":"67","author":"Kawasaki","year":"2017","journal-title":"Pathol. Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.micinf.2017.12.010","article-title":"Immune responses to congenital cytomegalovirus infection","volume":"20","author":"Britt","year":"2018","journal-title":"Microbes Infect."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/ncpneuro0401","article-title":"Herpesvirus infections of the nervous system","volume":"3","author":"Gilden","year":"2007","journal-title":"Nat. Clin. Pract. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Perera, M.R., Wills, M.R., and Sinclair, J.H. (2021). HCMV Antivirals and Strategies to Target the Latent Reservoir. Viruses, 13.","DOI":"10.3390\/v13050817"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.antiviral.2018.09.003","article-title":"New therapies for human cytomegalovirus infections","volume":"159","author":"Britt","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2040620720937150","DOI":"10.1177\/2040620720937150","article-title":"Letermovir and its role in the prevention of cytomegalovirus infection in seropositive patients receiving an allogeneic hematopoietic cell transplant","volume":"11","author":"Shigle","year":"2020","journal-title":"Ther. Adv. Hematol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/s40265-022-01677-4","article-title":"Maribavir: First Approval","volume":"82","author":"Kang","year":"2022","journal-title":"Drugs"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"223","DOI":"10.2147\/TCRM.S303052","article-title":"Evaluating the Safety of Maribavir for the Treatment of Cytomegalovirus","volume":"18","author":"Gandhi","year":"2022","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1128\/CMR.00009-10","article-title":"Antiviral Drug Resistance of Human Cytomegalovirus","volume":"23","author":"Lurain","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.coviro.2011.10.024","article-title":"Antiviral drugs and antiviral drug resistance","volume":"1","author":"Coen","year":"2011","journal-title":"Curr. Opin. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1002\/rmv.643","article-title":"Escape of herpesviruses from the nucleus","volume":"20","author":"Lee","year":"2010","journal-title":"Rev. Med. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/978-3-319-53168-7_7","article-title":"Herpesvirus Nuclear Egress","volume":"223","author":"Roller","year":"2017","journal-title":"Adv. Anat. Embryol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105875","DOI":"10.1016\/j.biocel.2020.105875","article-title":"Confined no more: Viral mechanisms of nuclear entry and egress","volume":"129","author":"Molenberghs","year":"2020","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e1934","DOI":"10.1002\/rmv.1934","article-title":"The human cytomegalovirus nuclear egress complex unites multiple functions: Recruitment of effectors, nuclear envelope rearrangement, and docking to nuclear capsids","volume":"27","author":"Marschall","year":"2017","journal-title":"Rev. Med. Viol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ceb.2016.12.007","article-title":"Getting to and through the inner nuclear membrane during herpesvirus nuclear egress","volume":"46","author":"Lye","year":"2017","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.15252\/embj.201592359","article-title":"Structural basis of membrane budding by the nuclear egress complex of herpesviruses","volume":"34","author":"Bigalke","year":"2015","journal-title":"EMBO J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"125","DOI":"10.21775\/cimb.041.125","article-title":"Nuclear Egress","volume":"41","author":"Draganova","year":"2021","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9150","DOI":"10.1128\/JVI.02530-14","article-title":"The Great (Nuclear) Escape: New Insights into the Role of the Nuclear Egress Complex of Herpesviruses","volume":"89","author":"Bigalke","year":"2015","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1099\/vir.0.83377-0","article-title":"Remodelling of the nuclear lamina during human cytomegalovirus infection: Role of the viral proteins pUL50 and pUL53","volume":"89","author":"Camozzi","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Marschall, M., Hage, S., Conrad, M., Alkhashrom, S., Kicuntod, J., Schweininger, J., Kriegel, M., Losing, J., Tillmanns, J., and Neipel, F. (2020). Nuclear Egress Complexes of HCMV and Other Herpesviruses: Solving the Puzzle of Sequence Coevolution, Conserved Structures and Subfamily-Spanning Binding Properties. Viruses, 12.","DOI":"10.3390\/v12060683"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Alkhashrom, S., Kicuntod, J., H\u00e4ge, S., Schweininger, J., Muller, Y.A., Lischka, P., Marschall, M., and Eichler, J. (2021). Exploring the Human Cytomegalovirus Core Nuclear Egress Complex as a Novel Antiviral Target: A New Type of Small Molecule Inhibitors. Viruses, 13.","DOI":"10.3390\/v13030471"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"27452","DOI":"10.1074\/jbc.C115.686527","article-title":"Crystal Structure of the Human Cytomegalovirus pUL50-pUL53 Core Nuclear Egress Complex Provides Insight into a Unique Assembly Scaffold for Virus-Host Protein Interactions","volume":"290","author":"Walzer","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1074\/jbc.RA119.011546","article-title":"High-resolution crystal structures of two prototypical beta- and gamma-herpesviral nuclear egress complexes unravel the determinants of subfamily specificity","volume":"295","author":"Muller","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/978-1-4939-2272-7_3","article-title":"Getting Across the Cell Membrane: An Overview for Small Molecules, Peptides, and Proteins","volume":"1266","author":"Yang","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/978-3-319-66095-0_13","article-title":"The Current Role of Cell-Penetrating Peptides in Cancer Therapy","volume":"1030","author":"Feni","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1002\/psc.2672","article-title":"Cell penetration: Scope and limitations by the application of cell-penetrating peptides","volume":"20","author":"Reissmann","year":"2014","journal-title":"J. Pept. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.jconrel.2019.07.020","article-title":"Cell-penetrating peptide: A means of breaking through the physiological barriers of different tissues and organs","volume":"309","author":"Xu","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_31","first-page":"414729","article-title":"Mechanisms of Cellular Uptake of Cell-Penetrating Peptides","volume":"2011","author":"Madani","year":"2011","journal-title":"Biophys"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"105231","DOI":"10.1016\/j.phrs.2020.105231","article-title":"Cell-penetrating peptides in oncologic pharmacotherapy: A review","volume":"162","author":"Vale","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.pharmthera.2015.07.003","article-title":"Cell-penetrating peptides transport therapeutics into cells","volume":"154","author":"Ramsey","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Habault, J., and Poyet, J.L. (2019). Recent Advances in Cell Penetrating Peptide-Based Anticancer Therapies. Molecules, 24.","DOI":"10.3390\/molecules24050927"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12964-021-00741-y","article-title":"Types of nuclear localization signals and mechanisms of protein import into the nucleus","volume":"19","author":"Lu","year":"2021","journal-title":"Cell Commun. Signal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5101","DOI":"10.1074\/jbc.R600026200","article-title":"Classical Nuclear Localization Signals: Definition, Function, and Interaction with Importin alpha","volume":"282","author":"Lange","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"16010","DOI":"10.1074\/jbc.272.25.16010","article-title":"A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus","volume":"272","author":"Brodin","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s00232-016-9940-z","article-title":"Progress in Research and Application of HIV-1 TAT-Derived Cell-Penetrating Peptide","volume":"250","author":"Zou","year":"2017","journal-title":"J. Membr. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.bpj.2010.03.065","article-title":"Cell-penetrating HIV1 TAT peptides can generate pores in model membranes","volume":"99","author":"Ciobanasu","year":"2010","journal-title":"Biophys. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4728","DOI":"10.1021\/bi900365s","article-title":"Cell-penetrating HIV1 TAT peptides float on model lipid bilayers","volume":"48","author":"Ciobanasu","year":"2009","journal-title":"Biochemistry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1099\/vir.0.052571-0","article-title":"The cytomegalovirus egress proteins pUL50 and pUL53 are translocated to the nuclear envelope through two distinct modes of nuclear import","volume":"94","author":"Schmeiser","year":"2013","journal-title":"J. Gen. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2560","DOI":"10.1016\/j.bmc.2013.02.030","article-title":"Systematic screening of the cellular uptake of designed alpha-helix peptides","volume":"21","author":"Usui","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1002\/(SICI)1099-1387(199904)5:4<185::AID-PSC184>3.0.CO;2-9","article-title":"Structural requirements for cellular uptake of \u03b1-helical amphipathic peptides","volume":"5","author":"Scheller","year":"1999","journal-title":"J. Pept. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.3762\/bjoc.14.116","article-title":"Design and biological characterization of novel cell-penetrating peptides preferentially targeting cell nuclei and subnuclear regions","volume":"14","author":"Gronewold","year":"2018","journal-title":"Beilstein J. Org. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Wei\u00dfenborn, L., Richel, E., H\u00fcseman, H., Welzer, J., Beck, S., Sch\u00e4fer, S., Sticht, H., \u00dcberla, K., and Eichler, J. (2022). Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23116309"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/9\/1040\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:14:10Z","timestamp":1760141650000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/9\/1040"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,23]]},"references-count":45,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ph15091040"],"URL":"https:\/\/doi.org\/10.3390\/ph15091040","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,23]]}}}